Pathophysiology

Medullary thyroid cancer (MTC) is usually diagnosed on physical examination as a solitary neck nodule, and early spread to regional lymph nodes is common. Distant metastases occur in the liver, lung, bone, and brain.

Sporadic MTC usually is unilateral. In association with multiple endocrine neoplasia (MEN) syndromes, it is always bilateral and multicentric. MTC typically is the first abnormality observed in both MEN 2A and 2B syndromes.

In addition to producing calcitonin, MTC cells can produce several other hormones, including corticotropin, serotonin, melanin, and prostaglandins; moreover, paraneoplastic syndromes (eg, carcinoid syndrome, Cushing syndrome) can occur in these patients.

Mutations in the RET (REarranged during Transfection) proto-oncogene, a receptor protein tyrosine kinase encoded on chromosome 10, have been classified into discrete subtypes, which confer varying degrees of risk[1] ; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality (see Prevention).

Epidemiology

Frequency

United States

Medullary carcinoma of the thyroid (MTC) constitutes approximately 4% of all thyroid cancers in the United States.[2] This figure translates into approximately 1000 diagnoses per year.

International

The international incidence of medullary carcinoma of the thyroid is similar to that in the United States.

Mortality/Morbidity

Isolated medullary carcinoma of the thyroid (MTC) typically demonstrates a relatively indolent biologic progression. While regional lymph node metastases are possible, the lesion may not spread outside of the cervical region until several months later. MTC associated with multiple endocrine neoplasia (MEN) syndromes may have a more aggressive course, which also depends on associated comorbidity (eg, pheochromocytoma).

Despite advances in genetic screening for the RET proto-oncogene, preliminary population studies have yet to show a definitive impact on disease prognosis.[3]

Age

Peak incidence of isolated medullary carcinoma of the thyroid (MTC) occurs in the fifth or sixth decade of life, and the peak incidence of MTC associated with multiple endocrine neoplasia (MEN) 2A or 2B occurs during the second or third decade of life.

Causes

Medullary carcinoma of the thyroid (MTC) has a genetic association with multiple endocrine neoplasia (MEN) 2A and 2B; however, it is heritable by a non-MEN mode of transmission. Sporadic MTC occurs in 75% of patients, and familial MTC constitutes the other 25%. Mutations in RET can lead to MTC development in cells derived from neural crest tissue.

Laboratory Studies

According to the American Thyroid Association, preoperative laboratory testing in patients with possible medullary thyroid carcinoma (MTC) has three purposes[1] :

To predict the extent of metastatic disease; this will determine the extent of preoperative imaging and may alter the surgical approach

In patients with MEN 2, to identify primary hyperparathyroidism and/or pheochromocytoma —comorbid conditions that alter the surgical approach and surgical priorities

To identify RET mutation carriers so that testing of appropriate family members can allow for early diagnosis and treatment of affected individuals

Calcitonin

Obtain serum calcitonin levels. Calcitonin is the principal biochemical marker in MTC; it is used for detection, staging, postoperative management, and prognosis.[1] The higher that the calcitonin levels are above normal, the greater the likelihood of MTC; basal levels of >100 pg/mL have been found to have 100% positive predictive value for MTC.[1, 4] Very rarely, patients with clinically apparent MTC may not have elevated calcitonin levels.

Occult MTC is rare, but clinically significant. If calcium stimulation testing cutoff data become well-validated, calcitonin screening is likely to be more widely used in the diagnostic workup for thyroid nodules in the United States.[5]

Machens et al found that in RET carriers who are at risk for MTC but have not yet undergone treatment, calcitonin levels can be used to determine the need for lymph node dissection.[6] In their study of 308 RET carriers, all patients with node-positive MTC had elevated basal calcitonin levels (91.4 pg/mL or higher); no patients with normal pretherapy calcitonin levels had lymph node metastasis. These researchers suggest that unless clinical evidence indicates a need for it, RET carriers with normal pretherapeutic basal calcitonin levels may forgo lymph node dissection.

Traditionally, a pentagastrin-induced rise in calcitonin secretion has been used to diagnose MTC; however, pentagastrin is not available in the United States and many other countries, and DNA testing for RET has replaced this diagnostic method in familial cases.

Screening studies in patients with MEN

Consider a 24-hour urinalysis for catecholamine metabolites (eg, vanillylmandelic acid [VMA], metanephrine) to rule out concomitant pheochromocytoma in patients with MEN type 2A or 2B. Pheochromocytoma must be treated before MTC.[1]

Obtain screening for the development of familial MTC in family members of patients with a history of MTC or MEN 2A or 2B. Screen all family members for missense mutation in RET in leukocytes. Finding a RET mutation in an asymptomatic family member should lead to discussion and pursuit of a prophylactic total thyroidectomy (see Treatment).

Imaging Studies

Patients in whom medullary thyroid carcinoma (MTC) is diagnosed or suspected on the basis of fine needle aspiration findings or calcitonin levels should undergo preoperative ultrasonography to detect lymph node metastases. The study should be performed by an experienced operator and should include the superior mediastinum and the central and lateral neck compartments.[1]

In a study of 134 patients with MTC, suspicious findings on preoperative ultrasonography were associated with disease aggressiveness. Patients judged to be at risk for malignancy on the basis of ultrasound (n= 89) more often had metastatic lymph nodes and extrathyroid invasiveness. Suspicious ultrasound results were significantly correlated with advanced stage disease, with an odds ratio of 5.5. Mean serum calcitonin values before and after surgery were significantly higher in the suspicious ultrasound group.[7]

Procedures

Histologic Findings

Grossly, medullary thyroid carcinoma (MTC) resembles a well-circumscribed off-white nodule with a rough texture. Microscopically, it contains nests of round or ovoid cells. A fibrovascular stroma is usually intercalated between cells. Sometimes, amyloid material, consisting of calcitonin prohormone, may occur in the MTC stroma. Perhaps most importantly, immunohistochemical diagnosis of MTC can be made by demonstrating calcitonin using radioactive calcitonin antiserum against MTC cells.

Staging

A 2009 article argued that using the 1997 TNM staging criteria is more accurate for medullary thyroid carcinoma than the 2002 criteria in terms of assessing prognosis. Under the 2002 criteria, a significantly higher percentage of patients were classified as having stage IV disease. The authors indicated that elevated calcitonin that remains stable often does not indicate a poor outcome, and patients with lymph node metastases but no distant disease would be better classified as having stage III cancer.[9]

Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer, noting that the discovery of particular genetic abnormalities in genetic tumors reveals specific targets for therapy. In particular, activating mutations of the RET tyrosine kinase receptor in medullary thyroid carcinoma makes MTC a good model for the use of small organic molecule tyrosine kinase inhibitors for treatment of metastatic disease. Clinical trials have shown promising results and tolerable toxicity.[10]

Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) for progressive, metastatic medullary thyroid cancer. These agents target various tyrosine kinases including MET, RET, and VEGFR-2.

The FDA approval of vandetanib is based on the results of the ZETA study, a phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). Participants randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.53; p< 0.0001). This difference reflects a 65% reduction in risk for disease progression. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted.[11, 12, 13]

Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic medullary thyroid carcinoma. A statistically significant prolongation in progression-free survival was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; p< 0.0001). Partial responses were observed only among patients in the active treatment arm (27% vs 0%; p< 0.0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months.[14]

In a 2009 retrospective review of elective superior mediastinal neck dissections for thyroid carcinomas, the authors concluded that "elective transcervical superior mediastinal dissection was commonly positive in patients with papillary, medullary, and anaplastic thyroid carcinomas. A transcervical approach may be safely performed without sternotomy to the level of the brachiocephalic vein." They pointed out that further studies are needed to determine the impact of elective superior mediastinal lymph node dissections on survival.[15]

Familial MTC

Prophylactic thyroidectomy is indicated for carriers of RET mutations who have no apparent disease but are at risk for aggressive MTC. Guidelines from the American Thyroid Association classify RET carriers into four risk levels, on the basis of the particular mutation involved. The age at which thyroidectomy is recommended corresponds to the level of risk and varies from as soon as possible within the first year of life (for those at highest risk) to beyond 5 years of age, provided that stringent criteria are met.[1]

Perform a total thyroidectomy with a central neck dissection or modified radial neck dissection for patients with clinically detectable disease evidenced by increased calcitonin levels, thyroid nodule on ultrasonography, or findings on physical examination. MTC is diagnosed after thyroidectomy in approximately 10-15% of cases.

Medication Summary

Although surgery remains the standard treatment for medullary thyroid carcinoma (MTC), several medications have entered clinical trials. For the most part, these are tyrosine kinase inhibitors that target vascular endothelial growth factor receptors. Partial response rates of up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more common.[17] For example, a phase II study of motesanib—a highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit—has been conducted in 91 patients with MTC. The objective response rate was low, but 81% of patients achieved stable disease during treatment.[18] In addition, sorafenib and sunitinib, which are approved for other malignancies, are being used selectively for patients who do not qualify for clinical trials.[17]

Vandetanib and cabozantinib are tyrosine kinase inhibitors approved by the FDA for treatment of symptomatic or progressive, metastatic medullary thyroid cancer.

Class Summary

Further Inpatient Care

Thyroid hormone therapy and radiotherapy are not as effective as surgical treatment for medullary thyroid carcinoma (MTC). However, positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy.

Further Outpatient Care

Measure calcitonin and carcinoembryonic antigen (CEA) levels after thyroidectomy. Patients with undetectable calcitonin — or, in patients with sporadic MTC who have undergone hemithyroidectomy, calcitonin levels within the normal reference range — should have follow-up testing every 6-12 months.

Detectable levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines. I f calcitonin becomes detectable after total thyroidectomy but imaging studies do not identify disease or if calcitonin levels rise after hemithyroidectomy, doubling time of calcitonin and CEA levels may be used to assess tumor progression.[1] In one study, 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease.[19]

Deterrence/Prevention

Management guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals with documented RET mutation who are at risk for aggressive medullary thyroid carcinoma.[1] The ATA has proposed schedules for the recommended age of RET testing, first ultrasound, serum calcitonin level, and prophylactic surgery, depending on the level of risk; in those at highest risk, surgery is recommended within the first year of life.

Complications

Permanent hypoparathyroidism and recurrent laryngeal nerve palsy reportedly occur in less than 2% of virgin neck dissections; however, reoperation is associated with a considerably higher risk of these injuries.

Prognosis

Prognosis depends on patient age, histologic grade, and status of surgical resection. Patients with a worse prognosis tend to be older, have higher-grade lesions, and have undergone incomplete surgical resection of the lesion.

A study by Rohmer et al concluded that disease-free survival (DFS) in younger patients (>21 y) with hereditary MTC was best predicted by TNM staging and preoperative basal CT level of less than 30 pg/mL.[20] Basal CT findings, class D genotype, and age were the key factors in deciding peroperatively timely surgery.

In a meta-analysis of 27 studies involving 984 MTC patients who underwent reoperation, Rowland and colleagues found that normalization of calcitonin after reoperation occurred in 16.2% of patients overall. Patients who underwent targeted selective lymph node removal procedures showed normalization of calcitonin in 10.5% of cases, while normalization was seen in 18.6% of those who underwent compartment-oriented procedures.[21]